The project will discover and investigate most of the transposable elements that have been adaptive during or after the migration of Drosophila melanogaster out of Africa. Transposable elements comprise an ubiquitous, extremely active and abundant part of eukaryotic genomes. Upward of 50% of the human genome, for example, is composed of transposable elements. Transposable elements are responsible for a large fraction of mutations of every type, from subtle regulatory mutations to gross genomic rearrangements. Recently, we have shown that transposable elements have been responsible for a large number of adaptive mutations in D. melanogaster. Here we will identify these TEs (estimated 30-60 in total) via computational work with wholly sequenced genomes of a number of D. melanogaster strains and via PCR measurements of frequency of these TEs in a number of North American and sub-Saharan African populations. For the TEs that are likely to be adaptive we will carry out tests of population differentiation across environmental gradients and will also test for the presence of signatures of positive selection in the flanking genomic sequences. We will determine the timing of the spread of these TEs using several population genetic approaches and will determine experimentally their effect on the regulation of neighboring genes. We will also use the functional annotation and molecular evolutionary and population genetic analyses of the genes adjacent to putatively adaptive transposable elements to shed light on which kinds of genes and processes are impacted by positive natural selection. Finally, we will use a panel of 192 isogenic strains, which are being fully sequenced and phenotyped for a large number of traits, to carry out association mapping of the phenotypic effects of all putatively adaptive and neutral TEs. We expect to detect consistent phenotypic effects for multiple independent adaptive mutations. In this way, we will not only identify multiple adaptive TE-derived mutations, describe their population genetic and evolutionary history, and investigate their molecular effects, but should also provide an insight into a key question in evolutionary biology -- which traits positive natural selection has been acting upon in the history of a species? PUBLIC HEALTH RELEVANCE: The transposable elements constitute much of the human genome and genomes of other organisms. They are also the most dynamic part of genomes, commonly generating genetic aberrations are often deleterious and cause disease. Understanding transposable element behavior is essential for understanding genomic and genetic determinants of human health.